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Boron-containing compounds as inhibitors of HIV proteinase

Authors: McNab, Donald;

Boron-containing compounds as inhibitors of HIV proteinase

Abstract

HIV Proteinase (HIV PR) has proved to be an excellent target for the development of anti-AIDS drugs. Four inhibitors of this enzyme are now approved for clinical use but they, like others, suffer from shortcomings associated with their size and the fact they are peptides. In this thesis the development of small non-peptidic cyclic compounds is described. They were designed to inhibit HIV PR principally by targeting its unique structural features rather than by mimicking its natural substrates. The designed compounds all contained the borinic acid functional group which it was anticipated would interact with the two critical aspartic acid residues of HIV PR. A heteroatom incorporated into these compounds was positioned in such a way that a water molecule which plays a pivotal role in the binding of the enzyme's substrates was displaced. Finally, two benzyl groups were incorporated; these were designed to mimic the side-chains of phenylalanine and tyrosine frequently found in the substrates of HIV PR. The borinic acid functional group has not previously been incorporated into HIV PR inhibitors. Therefore, an analogous series of five 2,6-dibenzylated-4-heterocyclohexanols, where the borinic acid group had been replaced by a hydroxyl group, were prepared and evaluated against the enzyme. These were prepared through bis aldol condensations followed by reduction of the carbonyl group in the bisenones that resulted from dehydration. Although low solubility prevented the analysis of three of these compounds and thereby their effectiveness, two of them were found to be moderately active. Having validated the design of the heterocyclic template, attempts were then made to synthesise borinic acid-containing analogues of these 4-heterocyclohexanols. The attempted syntheses of a directly comparable series of compounds, through application of both bismetallation and bishydroboration strategies, was unsuccessful. Instead, two acyclic diphenyl borinic acids were synthesised. Additionally, several related cyclic borinic acids and acyclic borinic and boronic acids consistent with the design strategy were prepared, from diphenyl sulfone, 2-bromodiphenyl ether and 2-bromodiphenyl sulfide, through the appropriate lithiated species formed by either lithium-hydrogen or lithium-halogen exchange. During the attempted syntheses of a cyclic borinic acid by selective oxidative cleavage of an organoborane derived from diphenyl sulfone, two highly novel borane-amine adducts were synthesised. None of the boron-containing compounds assayed against HIV PR were found to be inhibitors of the enzyme. This is thought to be as a result of the phenyl groups being directly attached to the boron atom, rather than being present in benzyl substituents as had been originally planned.

Country
United Kingdom
Related Organizations
Keywords

QP609.P7M6, Polygalacturonase, 540

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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